tbuckley/cabot-search huggingface dataset:
P923: TANDEM AUTOLOGOUS STEM CELL TRANSPLANTATIONS STILL BENEFIT FOR MYELOMA PATIENTS: A POOLING META-ANALYSIS
Authors: C.-H. Lee, C.-L. Ho
Journal: HemaSphere (2022)

Background: Although high-dose therapy and autologous stem cell transplant combined with novel agents continues to be the hallmark of first-line treatment in newly diagnosed transplant-eligible multiple myeloma patients, disease progression remains an issue. To deepen the treatment response and prolong disease free survival, tandem autologous stem cell transplant is one of treatment choice. Compared to toxicity of sub-sequent pharmacotherapy or allogeneic transplant, tandem ASCT is well-tolerated. However, the efficacy of tandem ASCT is not fully defined yet. Thus, we aimed to assess effectiveness of tandem ASCT. Aims: To evaluate the true effect of tandem autologous/autologous stem cell transplantation for myeloma patients in current era. Methods: Eligible randomized controlled trials published before Dec 2021 were retrieved from databases. Myeloma patients received tandem autologous stem cell transplantation was included. Systematic review and pairwise meta-analysis were performed. We calculated the hazard ratio (HR) with 95% confidence intervals (CIs). Results: Ten articles, involving 3,123 patients, met the selection criteria. All studies demonstrated acceptable quality. The mean age was 58.2 year-old with mean 36.2% high risk cytogenetics feature. Eight trials were international multi-centers phase III RCTs. Tandem autologous stem cell transplantation compared to single ASCT was associated with a significantly superior progression free survival (random-effect HR 0.89; 95% CI 0.82-0.97; I2 = 0.0%), but no significance difference regard to overall survival (random-effect HR 0.98; 95% CI 0.94–1.03; I2 = 0%). For high risk myeloma subgroup, 4 trials compared tandem ASCT versus lenalidomide, tandem ASCT demonstrated superior progression free survival (random-effect HR 0.87; 95% CI 0.82–0.91; I2 = 0%) Image:Summary/Conclusion: In conclusion, tandem ASCT are still to be considered as an acceptable treatment options in general myeloma patients. High-risk cytogenetics is frequently observed in newly diagnosed myeloma with worsens outcome after single autologous, whereas a tandem autologous transplant strategy may overcome onset poor prognosis.
Explainable Artificial Intelligence Methods in Combating Pandemics: A Systematic Review
Authors: Felipe Giuste, Wenqi Shi, Yuanda Zhu, Tarun Naren, Monica Isgut, Ying Sha, Li Tong, Mitali Gupte, May D. Wang
Journal: IEEE Reviews in Biomedical Engineering (2022)

Despite the myriad peer-reviewed papers demonstrating novel Artificial Intelligence (AI)-based solutions to COVID-19 challenges during the pandemic, few have made a significant clinical impact, especially in diagnosis and disease precision staging. One major cause for such low impact is the lack of model transparency, significantly limiting the AI adoption in real clinical practice. To solve this problem, AI models need to be explained to users. Thus, we have conducted a comprehensive study of Explainable Artificial Intelligence (XAI) using PRISMA technology. Our findings suggest that XAI can improve model performance, instill trust in the users, and assist users in decision-making. In this systematic review, we introduce common XAI techniques and their utility with specific examples of their application. We discuss the evaluation of XAI results because it is an important step for maximizing the value of AI-based clinical decision support systems. Additionally, we present the traditional, modern, and advanced XAI models to demonstrate the evolution of novel techniques. Finally, we provide a best practice guideline that developers can refer to during the model experimentation. We also offer potential solutions with specific examples for common challenges in AI model experimentation. This comprehensive review, hopefully, can promote AI adoption in biomedicine and healthcare.
P901: POMALIDOMIDE, BORTEZOMIB, AND DEXAMETHASONE IN LENALIDOMIDE–PRETREATED MULTIPLE MYELOMA: A SUBANALYSIS OF OPTIMISMM BY FRAILTY
Authors: A. Oriol, M. Dimopoulos, F. Schjesvold, M. Beksac, M. Yagci, A. Larocca, S. Guo, Y. Mu, K. Hong, S. Dhanasiri, P. Richardson, K. Weisel
Journal: HemaSphere (2022)

Background: Patients (pts) with multiple myeloma (MM) are likely to be older adults, and advanced age is associated with lower survival rates, in part due to comorbidities and frailty. Results from the phase 3 OPTIMISMM trial (NCT01734928) demonstrated that pomalidomide (P) in combination with bortezomib + dexamethasone (Vd) significantly improved progression-free survival (PFS) in lenalidomide (LEN)–pretreated pts with relapsed/refractory MM (RRMM) vs Vd, irrespective of age and Eastern Cooperative Oncology Group performance status (ECOG PS). Aims: Here, we report results from a post hoc analysis assessing outcomes of PVd vs Vd in pts with RRMM by frailty status. Methods: Pts with MM and 1–3 prior lines of therapy (including a LEN-containing regimen) who had been randomized 1:1 to PVd or Vd were assessed for frailty. Frailty scores were calculated using age (≤ 75 yr = 0; 76–80 yr = 1; > 80 yr = 2), the Charlson Comorbidity Index (≤ 1 = 0; > 1 = 1), and ECOG PS (0 = 0; 1 = 1; ≥ 2 = 2). Pts were classified as non-frail (NF; combined score: 0 or 1) or frail (F; combined score: ≥ 2). PFS, overall response rate (ORR), and safety outcomes were assessed by treatment group and frailty status. Results: In the intent-to-treat population (N = 559) (data cut-off Oct 26, 2017), 93/281 (33.1%) pts who received PVd and 93/278 (33.5%) who received Vd were frail. Baseline characteristics were similar between treatment groups within each frailty subgroup. Median PFS was longer with PVd vs Vd in NF (P = 0.001) and F (P = 0.006) subgroups (Table). ORR was higher with PVd vs Vd in NF (P < 0.001) and F (P < 0.001) subgroups. Incidence of grade ≥ 3 (G3) treatment-emergent adverse events (TEAEs) was higher with PVd vs Vd in NF (88.1 vs 61.3%) and F (96.8 vs 87.9%) subgroups; peripheral neuropathy, acute renal failure, and hypertension were the most common. Treatment discontinuation due to G3 TEAEs was greater with PVd vs Vd in NF (19.2 vs 18.5%) and F (30.1 vs 20.9%) subgroups. PVd had a longer median treatment duration vs Vd in NF (8.8 vs 5.7 mo) and F (8.9 vs 4.3 mo) subgroups. Image:Summary/Conclusion: Frail pts with RRMM who received PVd had longer PFS and higher ORR than pts who received Vd, consistent with the overall OPTIMISMM results. Frail pts experienced more G3 TEAEs and treatment discontinuations with PVd vs Vd, but treatment duration was longer with PVd vs Vd.
P1574: ANTINEOPLASTIC THERAPY FOR HEMATOLOGIC MALIGNANCIES DURING COVID-19
Authors: T. Chudnova, E. Baryakh, Y. Polyakov, T. Tolstykh, O. Kochneva, D. Ivanova, E. Misyurina, K. Yatskov, E. Zhelnova, M. Litvinenko, K. Kaluzhskaya
Journal: HemaSphere (2022)

Background: During the COVID-19 pandemic patients with hematologic malignancies frequently have to interrupt specific antineoplastic therapy as a result of a positive SARS-COV-2 RNA PCR result and for evidence of viral pneumonia on chest CT. However, delaying or withholding specific therapy for significant time may cause progression of a hematologic malignancy and increase the risks of tumor resistance. Aims: Analyze in-hospital overall survival and causes of death in COVID-19 patients during specific therapy for hematologic malignancies. Methods: During the period of March 2020 – November 2021, 192 patients with hematologic malignancies having coronavirus infection underwent specific antineoplastic therapy at the hematology unit of Moscow clinical hospital #52. We analyzed in-hospital overall survival and the causes of death, depending on the disease entity of a hematologic malignancy, disease status, patients’ age, Charlson comorbidity index and the intensity of specific antineoplastic therapy. The study included 93 patients with acute leukemias, 51 patients with non-Hodgkin’s lymphoma, 30 patients with chronic lymphocytic leukemia and 18 patients with multiple myeloma. Median age was 55 years (19-92 years). Results: In the acute leukemias group mortality was 25-82%, depending on the disease entity, disease status, age and intensity of the antineoplastic treatment. The most significant unfavorable prognostic factors were as follows: lack of acute leukemia remission (p=0.003), age above 65 years (p=0.002), Charlson comorbidity index > 6 (p<0,001). Infectious complications (24%) and severe coronavirus disease (60%) were the main causes of death in the acute leukemias group. In the group of patients who received chemotherapy for acute leukemia according to standard treatment protocols the rate of remission was higher, mortality was the lowest, and the risk of severe coronavirus disease was lower compared to patients who received specific antineoplastic therapy of lower intensity. In the non-Hodgkin’s lymphoma group mortality was 30%. In 90% cases of death patients had no remission of their underlying disease. Among the causes of death, the most common were lymphoma progression (46%) and severe COVID-19 (47%). In the chronic lymphocytic leukemia and multiple myeloma group in-hospital mortality was 27% and 17% respectively, and in 100% cases deaths were caused by severe coronavirus disease. Summary/Conclusion: The main risk factor for severe COVID-19 and death in patients with hematologic malignancies was lack of remission of the underlying disease. Therefore, specific antineoplastic therapy results in control over the neoplastic process, eventually reducing the risk of severe COVID-19. However, individual approach must be applied in the selection of antineoplastic treatment and its timing, and in evaluating the risks of coronavirus infection reactivation during immunosuppressive therapy.
S214: PHASE 1/2 STUDY OF ANBAL-CEL, NOVEL ANTI-CD19 CAR-T THERAPY WITH DUAL SILENCING OF PD-1 AND TIGIT IN RELAPSED OR REFRACTORY LARGE B CELL LYMPHOMA
Authors: W. S. Kim, S. J. Kim, S. E. Yoon, J. R. Kim
Journal: HemaSphere (2022)

Background: Anbal-cel is a novel 2nd generation autologous CD19 CAR-T cell therapy which has been knock-downed for PD-1 and TIGIT using OVIS platform. Anbal-cel demonstrated the eradication of CD19 positive tumor cells in vitro and in vivo better than conventional CD19 CAR-T cells. The knock-down of PD-1 and TIGIT at CD19 CAR-T cells exerts the superior T-cell functionality by delaying the exhaustion of CAR-T cells. Aims: This phase 1 dose escalation part (NCT04836507) was to evaluate the safety (DLT, MTD), PK and preliminary efficacy (objective response rate and duration of response) in patients with r/r LBCL. Anbal-cel was manufactured at GMP facility with fresh leukapheresis product. Methods: Patient was administered as a single intravenous dose at dose level 1 (2x105 cells/kg), dose level 2 (7x105 cells/kg) or dose level 3 (2x106 cells/kg). Lymphodepletion with cyclophosphamide (500mg/m2) and fludarabine (30mg/m2) was performed for 3 days prior to Anbal-cel infusion. Results: As of Jan 17 2022, 9 patients with r/r DLBCL were infused with Anbal-cel; 4pts at DL1, 3pts at DL2 and 2pts at DL2. Median age was 54 (range 26-71); all patients received 2 or more prior lines of therapy and 44% (4/9) received ≥4 prior line of treatment before the study. 78% (7/9) patients were refractory to their last treatment. 67% (6/9) of patients were at IPI 3-4 and 44% (4/9) of patients had bulky disease. No patient experienced DLT during the study. Of the 9 patients, 5 (56%) experienced CRS; 4 (44%) were grade 1 or 2 and one patient experienced grade 3 CRS. Median time to onset of CRS was 7 days (range, 1-16) with median duration of 4 days (range, 0-18). One patient dosed at DL3 experienced grade 2 ICANS, time to onset of ICANS was 7 days and lasted for 13 days. This patient had prior CNS involvement history before the study. Most commonly reported grade 3/4 AEs were neutrophil count decrease (6/9, 67%), anemia (5/9, 56%), thrombocytopenia (2/9, 22%), platelet count decrease (2/9, 22%) and no infection was reported. Complete response rate (CRR) was 78% and complete responses were observed at the lowest dose level and from patients expressing less than 10% CD19 at IHC; 3 complete responses (CR) at DL1, 2 CRs at DL2 & DL3 respectively. Dose-dependent CRC01 expansion was observed; median Tmax was 15.4, 15.8, 11.0 days at DL1, DL2 & DL3 each; median Cmax was 18,003, 30,103, 53,688 copies/ug gDNA at DL1, DL2 & DL3 each; median AUC0-28day was 679,125, 1,110,108, 2,852,235 copies/ug gDNA at DL1, DL2 & DL3 respectively. Summary/Conclusion: Anbal-cel demonstrated promising efficacy and tolerable safety profile in this dose escalation study. Based on this phase 1 study, phase 2 patient enrollment will be commenced in Mar 2022 to evaluate the response rate, duration of response of CRC01 as well as safety. In addition, various biomarker studies are planned to investigate the differential mode of action of Anbal-cel during phase 2 study.
P1619: PLATELET TRANSFUSION THRESHOLDS FOR PEDIATRIC PATIENTS; ARE WE FALLOWING THE GUIDELINE?
Authors: H. Alsulami
Journal: HemaSphere (2022)

Background: Platelet threshold of 10x109 /L is recommended for clinically stable thrombocytopenic pediatric patients. Transfusions at a higher level (given the absence of research evidence, as determined by clinical circumstances, generally at threshold of 40x109 /L) may be required for patients with signs of bleeding, high fever, hyper-leukocytosis, rapid fall in platelet count, concomitant coagulation abnormality, critically ill patients, and those with impaired platelet function (including drug induced). Transfusions at a higher level may be also required for patients undergoing invasive procedures. Aims: the aime of this study is to check if the phycisions follow the guidelines for platelet transfusion Methods: This study is a retrospective observational analysis of platelet transfusion thresholds in a single secondary pediatric hospital in Riyadh. From the blood bank database, the list of the patients who received platelet transfusions in the second half of 2018 was retrieved. Patients were divided into two groups; group A, those belong to the category of high platelet level for transfusion (such as those with bleeding, high fever, rapid fall in platelet count, impaired platelet function or undergoing invasive procedures) and group B, those who were not. Then we looked at the pre and post transfusion platelet levels for each group. The data was analyzed using GraphPad software and the data expressed as Mean ± SD. Results: A total of 112 of transfusion episodes in 61 patients (38% female) were analyzed. The age ranged from 24 days to 8 years. The distribution of platelet transfusion episodes was 64% (n=72) for group A and 36% (n= 40) for group B. The mean pretransfusion platelet count was 46x103 ± (11x 103) for group A and 28x103 ± (6x103) for group B. the post-transfusion mean platelet count was 61 x 103 ± (14 x 103) and 60 x103 ± (24 x 103) for group A and B respectively. Among the groups the rise in the mean platelet count after transfusion was significant among stable patients (group B) compared to unstable patients (group A) (P < 0.001). Summary/Conclusion: he platelet count threshold for transfusion varied with the clinical condition and is higher among unstable patients’ group which is expected. For stable patients the threshold was higher than what it should be which means that the clinicians don’t follow the guidelines in this regard. The rise of platelet count after transfusion was higher among stable patients.
PB2216: VACUOLES APPEAR IN RED BLOOD CELLS TRANSFUSED TO PATIENTS WITH SICKLE CELL DISEASE-RELATED HYPOSPLENISM
Authors: L. Dumas, A. Sissoko, A. Fricot, N. Salama, L. Joseph, S. Manceau, S. Dokmak, A. Michel, B. Maitre, C. Gachet, M. Cavazzana, C. Roussel, P. Buffet
Journal: HemaSphere (2022)

Background: Defective spleen function (hyposplenism) affects subjects with sickle cell disease (SCD) and is associated with complications. Red blood cell (RBC) alterations are very accurate markers of spleen function. Vacuole-containing RBC (pocked RBC) circulate in high proportions (10 to 70%) in the blood of hyposplenic subjects while their proportion does not exceed 5% of RBC in healthy subjects. Vacuoles in pocked RBC are generally considered as remnants of organelles in erythroblasts. Aims: The aim is to determine the origin of vacuoles Methods: Patients with SCD who benefit from an exchange transfusion program, have not only their own HbSS RBC but also transfused HbAA RBC in circulation. In vitro sickling “Emmel test” discriminates HbSS RBC that sickle, from HbAA RBC that do not sickle. We perfused a mixture of HbSS RBC and HbAA RBC (from exchange transfusion left-overs) into human spleens ex-vivo. We then analyzed spleen sections and quantified vacuoles in RBC containing hemoglobin polymers or not. Results: Using Emmel Test, we observed vacuoles in HbSS RBC but also in transfused HbAA RBC. Vacuoles in HbAA RBC were more frequent in transfused SCD patients than in healthy subjects (25.1±4.41% vs. 2.8±2.1%). In our experimental ex vivo perfusion, most RBC without hemoglobin polymers is HbAA RBC. We observed a high rate of vacuoles in both polymerized and non-polymerized RBC (29.8±3.7% vs. 17.9±5.8%). Summary/Conclusion: Taken together, these results strongly suggest that vacuoles are created de novo in transfused HbAA RBC. Counting vacuoles in RBC labeled with anti-HbS and anti-HbA antibody is ongoing to validate these observations. When the spleen is dysfunctional, these pocked RBC stay in circulation hence their validity as a spleen function marker. De novo appearance of vacuoles in transfused HbAA RBC likely impacts the kinetics of reappearance of pocked RBC in circulation following regular or exchange transfusion of hyposplenic subjects, and opens interesting prospects on cell processes involved in their genesis.
S172: FUNCTIONAL SUBSETS OF PLASMA CELLS ASSOCIATED WITH AMYLOID PRODUCTION AND
Authors: X. Wang, H. Han, J. Sun, Q. Wang, X.-M. Gao, K.-N. Shen, L. Zhang, Y. Zhao, X.-X. Cao, M. Qian, Y. Chen, J. Li
Journal: HemaSphere (2022)

Background: Light chain amyloidosis (AL amyloidosis, AL) is a life-threatening plasma cell dyscrasia characterized by misfolded monoclonal immunoglobulin light chain production by pathogenic bone marrow plasma cells (BMPCs), leading to irreversible damage in multiple organs. Until now, the pathogenic BMPCs in AL haven’t been elucidated, let alone the functional roles of BMPC subsets. Aims: We aimed to identify intra- and inter-individual heterogeneities in BMPCs, especially those related to AL development, light chain production, organ tropism, and chemotherapy response. Methods: Here, we conducted single-cell RNA sequencing and image flow cytometry analysis of BMPCs from patients with AL (n=3), compared with that from monoclonal gammopathy of undetermined significance (MGUS) (n=2) and healthy controls (n=21). All the subjects provided informed consent. Results: We identified 7 functional subsets of BMPCs in AL, MGUS or healthy controls (Fig. 1a). These subsets had over-lapping but distinct functions, including DNA repair, cell proliferation, drug response, osteoclast differentiation, and immunoglobulin production (Fig. 1b). Subsets enriched in AL showed up-regulation of amyloidosis-associated genes (Fig. 1c), such as the amyloid-beta binding protein-encoding Apolipoprotein E (APOE), and showed plasmablastic morphology (Fig. 1d). Subsets defined by aberrant light chain production up-regulated the pathways related to neutrophil degranulation, transportation to and modifications in the Golgi apparatus, and asparagine N-linked protein glycosylation. High expression of Cyclin D1 (CCND1), CD79A, and V-Set Pre-B Cell Surrogate Light Chain 3 (VPREB3) were observed in the predominant subset of AL predicted sensitive to venetoclax, while Cyclin D2 (CCND2), S100 Calcium Binding Protein A6 (S100A6), Cystatin C (CST3) were up-regulated in that of AL predicted resistant (Fig. 1e). In an independent cohort of bulk RNA sequencing (n=29), clinical subgroups of patients with AL were defined by the proportion of functional subsets, including 2 major subgroups that were consistent with the aforementioned AL with differential sensitivity to venetoclax (Fig. 1f). Co-expression of CCND1, CD79A, and VPREB3, and a larger predominant subset, were in the venetoclax-sensitive subgroup. The up-regulation of CCND2 and amyloidosis-associated genes, including S100A6 and CST3, were in the venetoclax-resistant subgroup (Fig. 1g). Image:Summary/Conclusion: These functional subsets of BMPCs provide mechanistic insights into AL pathogenesis, light chain production, and chemotherapy response. These results suggest potential avenues for the exploration of clinical subgroups among AL patients.
PB2240: SILENT GLOBIN MUTATIONS. 10 YEARS REFERRALS FOR GENETIC COUNSELING.
Authors: S. Theodoridou, A. Teli, E. Boutou, E.-E. Delaki, E. Yfanti, V. Efthimia, E. Zarkada, A. Balassopoulou
Journal: HemaSphere (2022)

Background: Haemoglobinopathies, constitute the most frequent monogenic disorders worldwide and in Greece. Silent β and α globin mutations may be missed during screening programs. The identification of combinations of silent defects with severe thalassemia mutations is essential for the genetic counseling of at-risk couples. Aims: We report the results of the molecular analysis of 241 subjects with borderline hematologic indices or HbA2 levels respectively, without iron deficiency, during a ten year period in order to provide the appropriate genetic counseling for couples at-risk. Methods: The screening methodology of identifying the carriers is simple and low cost based on determination of red cell indices (RBC, Hb, Ht, MCV, MCH, RDW) and quantification of HbA, F, A2, S, C, and other haemoglobins with the HPLC (Bio-Rad Variant Haemoglobin Testing System) and Capillary electrophoresis (Minicap). The practice guidelines are similar throughout the prevention network laboratoties of the country. The screening methods used for DNA analysis, all performed in the National Thalassemia Centre, were denaturating gradient gel electrophoresis (DGGE), allele-spesific oligonucleotide (ASO) analysis, high resolution melting analysis and other polymerace chain reaction directed methods and DNA sequencing. Results: 162 subjects (67,2%) were found carriers of a silent thalassemic mutation. Among the subjects with MCH<27,5 pg, we found 147(89%) with a silent mutation. Most common was the -α 3.7, -101(C>T) (68,7%). Other α deletions were found and some unstable variants as Ηb Icaria, Hb Adana, Hb Agrinio, Hb Constant Spring, triplication of α genes and Termination Cd +6 C-G in the 3’ untranslated region (3’UTR of the β-globin gene (+1480 C→G) and silent Cap+1570(T>C) (HBB:c*96T>C),. Among 76 subjects with borderline Hb A2 values (3,1-3,9%), 29 (39%) had a molecular defect in the β or α-globin genes. No molecular defects were found in the remaining 47 individuals. Among the positive samples the most common silent mutation was the-101(C>T)(n=15). In our study group the -101 (C>T) mutation shows an elevated Hb A2, Term+ 6 and silent Cap+1570(T>C) (HBB:c*96T>C), have a phenotype closer to normal. The -α3,7 deletion can be suspected when MCH is below 27,5 and triplication of a genes (ααα anti–3.7/αα) is often silent. Summary/Conclusion: Current application of molecular techniques to the study of borderline heamatologic measurements is important in the field of thalassemia diagnosis and the genetic counseling of couples at risk.